Project Summary Resistance to existing antimicrobial drug classes continues to spread in bacterial pathogens of man and other animals. The pipe-line of new antimicrobials or their alternatives is limited, and the timeline is uncertain. The Centers for Disease Control and Prevention have stated the risk of ?running out of drugs to treat serious Gram-negative infections?. Of these, nontyphoidal Salmonella enterica infections cause thousands of hospitalizations and hundreds of deaths annually in the U.S. and are often foodborne. The first-line treatment choices for serious salmonellosis are fluoroquinolones (ciprofloxacin) and extended-spectrum cephalosporins (ceftriaxone). The current treatment regimens were designed using the pharmacodynamic, PD, data for the pathogen strains that were highly susceptible to the drugs; the regimens are ineffective against the strains with reduced susceptibility that continue to spread. Recent experimental data show there may be predictable and consistent changes in an antimicrobial's PD for the reduced susceptibility strains compared to the susceptible strains within a pathogen species. Also, all relevant PD parameter values change, not only the drug minimum inhibitory concentrations for the strains (which is often the only metric considered in making decisions about the regimens). This signals a possibility the treatment regimens for existing antimicrobials could be modified to cure infections by the strains that have acquired reduced susceptibility. The long-term objective is to determine the PD changes between the susceptible and reduced susceptibility strains of pathogens in which antimicrobial resistance is of biggest concern, to enable design of the modified treatment regimens. The specific objective for this proposal is to determine the PD changes in nontyphoidal S. enterica for the two first-line antimicrobials. The first aim is to determine the PD parameter value changes for ciprofloxacin between S. enterica strains that are susceptible, and that carry genetic determinants of reduced fluoroquinolone susceptibility most often detected in this foodborne pathogen in the U.S. The second aim is to determine the PD parameter value changes for ceftriaxone between S. enterica strains that are susceptible, and that carry genetic determinants of reduced cephalosporin susceptibility most often detected in this foodborne pathogen in the U.S. The third aim is to investigate whether the PD changes in the S. enterica strains that have just acquired fluoroquinolone or cephalosporin resistance via horizontal plasmid transfer are similar to those in circulating field strains that acquired such resistance at an earlier time. Thus, the project will provide the ground data on the PD changes between the susceptible and reduced susceptibility strains of nontyphoidal S. enterica for the two first-line treatment choices: the fluoroquinolone ciprofloxacin and the extended spectrum cephalosporin ceftriaxone. This will enable the research team to evaluate how the treatment regimens could be modified to cure infections by the pathogen strains that have acquired reduced susceptibility to these drugs, and thus to prolong the usable life-span of these critically important antimicrobials.